ClinVar Miner

Submissions for variant NM_000091.4(COL4A3):c.4981C>T (p.Arg1661Cys) (rs201697532)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516971 SCV000612952 pathogenic not provided 2014-11-25 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000283598 SCV000537703 likely pathogenic Alport syndrome, autosomal recessive 2016-07-11 criteria provided, single submitter clinical testing This heterozygous missense variant in the COL4A3 gene (autosomal recessive transmission) is present in a male patient with Alport syndrome who also harbours a non-sense variant in the same gene (see below). The segregation analysis could not be done, but regarding the clinical presentation of the patient, it is assumed that these two variants are present in compound heterozygosity
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000516971 SCV000341862 likely pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000516971 SCV000809140 pathogenic not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000516971 SCV000947691 pathogenic not provided 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1661 of the COL4A3 protein (p.Arg1661Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201697532, ExAC 0.05%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in an individuals affected with Alport syndrome (PMID: 24052634). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been observed in several individuals with Alport syndrome (PMID: 26809805, 11134255). ClinVar contains an entry for this variant (Variation ID: 287915). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000677316 SCV000803483 uncertain significance Alport syndrome 3, autosomal dominant 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Alport syndrome, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:24052634). BS2-Supporting => BS2 downgraded in strength to supporting.

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